The Journal of Steroid Biochemistry and Molecular Biology
Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS)☆
Introduction
It is becoming increasingly evident that the gonadal steroid hormone estrogen imparts a multifaceted influence over synaptic transmission in the mammalian central nervous system. Not only can estrogen alter synaptic responses via genomic mechanisms, but there is a wealth of information that indicates the steroid can also modulate cell-to-cell communication much more rapidly (for review see [1]. These synaptic alterations are brought about via changes in the cellular responsiveness to the activation of various receptor systems (both G protein-coupled and ionotropic) to their respective first messengers. For example, estrogen can modulate the cellular responsiveness to ionophoric glutamate (both N-methyl-d-aspartate (NMDA) and non-NMDA) receptor activation [2], [3]. In addition, it can alter the linkage of G protein-coupled receptor systems such as opioid (both μ and κ), γ-aminobutyric acid (GABA)B and dopamine D2 receptors to their respective effector systems [4], [5], [6], [7], [8]. Furthermore, it now appears that the steroid can function as a first messenger by activating an estrogen receptor that couples directly to K+ and Ca2+ channels by way of a pertussis toxin-sensitive G protein [9], [10]. These fundamentally distinct signaling pathways give rise to a coordinated regulation by estrogen of complex physiological processes such as reproduction, stress responses, feeding and cognition. We will focus on the estrogenic modulation of K+ channel activity in hypothalamic neurons involved in many of these physiological processes.
Section snippets
G protein-coupled inwardly-rectifying K+ (GIRK) channels
One of the principal actions of estrogen is to regulate the output of gonadotropin-releasing hormone (GnRH) from the mediobasal hypothalamus and hence the reproductive cycle. Although, we demonstrated direct actions of estrogen to inhibit GnRH neuronal activity over 15 years ago [9], [11], it has been only recently that estrogen receptors have been demonstrated in GnRH neurons [12], [13], [14]. In fact, estrogen responsiveness has been conferred to neurons closely juxtaposed to the GnRH cells
Activation of protein kinases
What is the underlying cause of this estrogen-induced decrease in the responsiveness of POMC neurons to the μ-opioid receptor-mediated activation of an inwardly-rectifying K+ channel or the potentiation of the α1-adrenergic inhibition of the SK current? One insight comes from studies that have examined μ-opioid receptor desensitization and opiate tolerance, both of which are associated with a refractoriness to μ-opioid receptor agonists, have implicated intracellular protein kinase pathways in
Significance
Estrogen modulates the excitability of a number of neurons that are involved in the control of homeostasis, including reproduction, stress responses, feeding and motivated behaviors. Recently, we have gained some insight into the cellular mechanisms by which estrogen exerts its effects on these neurons. First of all, estrogen negatively modulates the coupling of the μ-opioid and/or GABAB receptors to their effector K+ channel in β-endorphin, dopamine and GABAergic neurons. This uncoupling
Acknowledgements
The experiments described in this review were supported by US Public Health Service Grants NS 35944, NS 38809, DA 05158 and DA 00192 (Research Scientist Development Award to MJK). The authors would like to recognize Ms. Martha, A. Bosch and Mr. Barry R. Naylor for their expert technical contributions to these studies.
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Proceedings of the 15th International Symposium of the Journal of Steroid Biochemistry and Molecular Biology, “Recent Advances in Steroid Biochemistry and Molecular Biology”, Munich, Germany, 17–20 May 2002.